Despite decades of research efforts, cancer remains today's most pressing health concerns. Current cancer therapies primarily focus on surgical resection, radiotherapy, and chemotherapy. Radiation therapy and many chemotherapeutic compounds trigger the intrinsic apoptotic pathway by inducing DNA damage and cellular stress, which block DNA replication and inhibit tumor cell division. These conventional therapies, however, often cause systemic toxicity and become ineffective when resistant tumors emerge.
Recently, attention has been focused on a new generation of drugs targeting tumor-related biological molecules, such as Traztuzumab, a monoclonal antibody that targets the human epidermal growth factor receptor (HER-2) in breast cancer. In addition, induction of extrinsic apoptotic pathway has been noted as a promising approach of tumor therapy. Tumor necrosis factor (TNF) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) are recently discovered targeted therapeutics. TRAIL is a member of the tumor necrosis factor (TNF) cytokine family that induces apoptosis upon binding to its death domain containing receptors TNF receptor (TNFR), TRAIL receptor 1 (TRAIL-R1, also known as death receptor 4 or DR4) and TRAIL receptor 2 (TRAIL-R2, also known as death receptor 5 or DR5). TRAIL binds to TRAIL-R1 and TRAIL-R2 and triggers TRAIL-induced apoptosis. Upon binding to their respective receptors, TNF and TRAIL trigger trimerization of the death receptors and recruitment of death domain-containing mediator proteins. The cascade of protein activation leads to the activation of the initiator caspase, caspase 8, and subsequently the effector caspases, which act on the death substrate in apoptosis.
So far, five TRAIL receptors have been discovered: two are agonist receptors TRAIL-R1 and TRAIL-R2 and three are antagonistic receptors TRAIL-R3 (also known as decoy receptor 1, DcR1), TRAIL-R4 (DcR2) and osteoprotegerin. DcR1 and DcR2 as decoy membrane receptors can bind to TRAIL, but cannot transmit the apoptotic signal because they do not contain functional intracellular death domains. Osteoprotegerin is a secreted TNF receptor family member and may be a soluble antagonist receptor for TRAIL.
Tumor therapy using purified recombinant TRAIL has entered clinical trials. The prospects of recombinant TRAIL anti-cancer therapy, however, have been dampened by reports of hepatotoxicity and tumor resistance. Although TRAIL preferentially induces apoptosis in cancerous cells than normal cells, not all tumor cells are sensitive to TRAIL. The basis for the resistance may be multifaceted, ranging from the competition of decoy receptors for TRAIL binding to up-regulation of NF-κB, an anti-apoptosis factor induced by TRAIL signaling. Though it has been proposed that combination of recombinant TRAIL therapy with traditional chemotherapy or radiation therapy may overcome TRAIL resistance, the non-selective nature of the conventional therapies may cause damages to normal cells.
TRAIL-R1 and TRAIL-R2 agonistic antibodies have been developed and under clinical trials with the hope that the specificity for death receptors may eliminate tumor resistance resulted from decoy receptor competition. The generation of antibodies or humanized antibodies, however, is time consuming and cumbersome. In addition, tumor resistance caused by death receptor mutations that abolish antibody binding to the receptors has been reported. See Lee et al. 1999, Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers, Cancer Research 59(22):5683-6, and Dechant et al., 2004, Mutation analysis of the apoptotic “death-receptors” and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines, Int. J. Cancer 109:661-667.
Thus, there exists a need in the art for a more effective and adaptable anti-tumor therapy based on the death receptors induced extrinsic apoptosis pathway.